title: Regulation of megalin expression in cultured proximal tubule cells by angiotensin II type 1A receptor- and insulin-mediated signaling cross talk.
abstract: Impairment of proximal tubular endocytosis of glomerular-filtered proteins including albumin results in the development of proteinuria/albuminuria in patients with chronic kidney disease. However, the mechanisms regulating the proximal tubular function are largely unknown. This study aimed to investigate the role of angiotensin II type 1A receptor (AT(1A)R)- and insulin-mediated signaling pathways in regulating the expression of megalin, a multiligand endocytic receptor in proximal tubule cells (PTCs). Opossum kidney PTC-derived OK cells that stably express rat AT(1A)R but are deficient in endogenous angiotensin II receptors (AT(1A)R-OK cells) were used for this study. Treatment of the cells with angiotensin II suppressed mRNA and protein expression of megalin at 3- and 24-h incubation time points, respectively. Cellular uptake and degradation of albumin and receptor-associated protein, megalin's endocytic ligands were suppressed 24 h after angiotensin II treatment. The AT(1A)R-mediated decrease in megalin expression was partially prevented by ERK inhibitors. Insulin competed with the AT(1A)R-mediated ERK activation and decrease in megalin expression. Inhibitors of phosphatidylinositol 3-kinase (PI3K), a major component of insulin signaling, also suppressed megalin expression, and activation of the insulin receptor substrate (IRS)/PI3K system was prevented by angiotensin II. Collectively the AT(1A)R-mediated ERK signaling is involved in suppressing megalin expression in the OK cell line, and insulin competes with this pathway. Conversely, the insulin-IRS/PI3K signaling, with which angiotensin II competes, tends to stimulate megalin expression. In conclusion, there is AT(1A)R- and insulin-mediated competitive signaling cross talk to regulate megalin expression in cultured PTCs.
authors.affiliation: Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hosojima
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Sato
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kaseda
authors.forename: Taeko
authors.initials: T
authors.lastname: Soma
authors.forename: Asako
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Akiyo
authors.initials: A
authors.lastname: Suzuki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kabasawa
authors.forename: Aya
authors.initials: A
authors.lastname: Takeyama
authors.forename: Kenji
authors.initials: K
authors.lastname: Ikuyama
authors.forename: Noriaki
authors.initials: N
authors.lastname: Iino
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Thekkumkara
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Takeda
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Fumitake
authors.initials: F
authors.lastname: Gejyo
authors.forename: Akihiko
authors.initials: A
authors.lastname: Saito
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases